Harnessing T-cells to treat cancer more effectively remains a leading biomedical research goal, yet this pursuit is often thwarted by multiple obstacles, including poor antigen presentation and negative immunoregulatory mechanisms within the tumor and its microenvironment. This program project grant (PPG) renewal builds on successes during the past funding period to address several persistent problems that impede the use of T cells as Immunotherapy for poor-prognosis solid tumors: (I) abbreviated expansion and persistence of activated T cells, (ii) negative impact of the tumor microenvironment, and (iii) lack of an adequate molecular safety switch to destroy aberrantly proliferating T cells. Thus, investigators with exemplary records of interactive research have designed first-in-man studies that would each address one or more of these issues. Project 1 tests the use of VZV vaccination to boost the expansion and antitumor activity of VZV-specific cytotoxic T lymphocytes (CTLs) engrafted with a GD2-directed chimeric antigen receptor (CAR) in patients with relapsed/refractory sarcomas. Project 2 seeks to develop effective targeted T-cell therapy for pancreatic cancer by using T cells that are specific for the tumor antigen mesothelin and express a hovel chimeric cytokine receptor (1L4/7), which is expected to promote T-cell expansion and persistence when engaged by inhibitory IL4 signal from the tumor. Project 3 will take advantage of recent successes with the use of CAR.GD2+ T cells in treatment of advanced neuroblastoma to produce a new generation of modified T cells. The investigators will engineer two costimulatory endodomains, CD28 and OX40, as well as an inducible suicide gene {iC9), into the CAR construct and analyze the consequent effects on T-cell proliferation and tumor killing in patients with relapsed/refractory neuroblastoma. Project 4 asks whether targeting multiple antigens on nasopharyngeal cancer cells and expressing a dominant-negative TGF-beta receptor will broaden the specificity and enhance the durability of EBV-specific CTLs directed to this tumor. Besides initial clinical testing of promising therapeutic strategies, these projects will also assess newly emerging concepts in a range of model systems, in preparation for subsequent phase I testing. A major strength of this proposal resides in the GMP Core, where improvements in the T-cell manufacturing process will enable all planned studies to be completed in a timelier and less costly manner. This series of iterative laboratory and linked clinical studies is expected to yield strategies with the potential to increase cure rates and reduce treatment-related toxicity in patients with a spectrum of resistant solid tumors.